Pyrazine derivatives and method of preparing the same



Patented May 4, 1954 I UNITED STATES PATENT OFFICE PYRAZINE DERIVATIVESAND METHOD OF PREPARING THE SAME Victor K. Smith, Jr., Pearl River, andSamuel Knshner, Nanuet, N. Y., assignors to American Cyanamid Company,New York, N. Y., a corporation of Maine No Drawing. Application duly 22,1952,

Serial No. 300,336

8 Claims. (01. 260-250) 1 2 V This invention relates to mono-substitutedous layer is extracted with a solvent, such as di- 1 pyra M part u ly,it r s to su st ethyl ether. The ether can be concentrated and ftuted-Z-carbonyl pyrazine. the desired compound crystallized out or theThe role of vitamins in nutrition is well known ether can be removed andthe product distilled.

and assumes greater importance as new informa- The reaction of thepresent invention may be tion is made available concerning theparticular carried out at a temperature of to 0.

function of each. Recently it has been found The reaction is complete infrom about a feW that folic acid was effective in curing macrocyticminutes up to about two hours. anemias and other blood conditions. Also,oom- The process of the present invention is depounds which are folicacid antagonists, such as .o scribed in greater particularity by thefollowing aminopterin, have been found useful in treating specificexamples which are given by Way of i1- ahnormal blood conditions such asleukemia. lustration and not limitation. It is well established thatnicotinamide is an im- Emample 1 portant vitamin of the B complex groupand. its deficiency is the specific cause of pellagra. 13 Exactly 55gms. es) o ma es u tu We have now found that certain substituted s isp1aced in a y, three-necked, roundpyrazines hereinafter defined have theproperty bottomed flask fitted with a mercury-sealed stirof inhibitingthe nicotinamide response of L. r, a flux condenser and ryi u adropmabinosus and exhibit an antagonistic effect on nine funnel, and aremovable ice bath. Then nicotinamide growth response in chicks. The 2933 em moles) of methyl iodide is dissolved compounds therefore assumeimportance in exin 50 of anhydrous ether i a y Erlenmeyer perimentalmedicine and nutrition since vitamin flask. A small portion o s t er sout o is deficiency symptoms may result from the presintroduced into theround-bottomed flask along ence of antagonists as well as from theabsence With minute iodine y AS 500R as the of the vitamin. 5 reactioncommences, 200 ml. of anhydrous ether The compounds of the presentinvention may is added. With 810W stirring, the remainder of beillustrated by the following general formula: the methyl iodide50111171011 is w dd dr p- 0 wise just rapidly enough to maintainvigorous %N\ u T refluxing. After complete formation of the Q Grignardreagent, the mixture is cooled by means L of the ice bath and then 12gms. (1 mole) of cyanopyrazine dissolved in 50 ml. of anhydrous ether isadded dropwise. During this addition the temperature of the mixture iskept at 05 C. by use of the ice bath and vigorous stirring ismaintained. A solid precipitates from solution during this addition.Cold water is then added slowly with vigorous stirring until theprecipitate has dissolved. The ice bath is used to keep the mixturecool. The entire liquid mixture is then transferred to a separatoryfunnel and the two liquid layers are separated. The aqueous residue,after saturation with potassium chloride, is washed twice with ether andthe ether washes are added to the original ethereal extract. Thecombined other solutions are dried with anin which R is an alkyl or arylradical.

These compounds are crystalline solids or relatively high boilingliquids. They are soluble in ether, chloroform, carbon tetrachloride,etc. and somewhat soluble in water.

The compounds of the present invention are prepared by reactingcyanopyrazine with an "3 1 or aryl magnesium iodide or bromide in to thepresence of an anhydrous solvent.

The intermediates used in the process of the present invention may be,for example, methyl iodide, ethyl iodide, propyl iodide, butyl iodide,methyl bromide, ethyl bromide, propyl bromide, butyl bromide,bromobenzene, iodobenzene, bromonaphthalene,iodonaphthalene, and thelike. hyfimus .magnesium Sulfate and filtered The In earrying out theprocess of the present filtrate is concentrated to small volume andvention the oyanopyrazine is mixed with the cooled thereby causing thez'acetylpyrazme to desired intermediate under anhydrous conditionscrystallize o olut o in an anhydrous solvent at a temperature below 5 C.The product separates as a solid complex which is decomposed by water orice. Follow- T0 20 sof blomobenzene in 50 Of ie y ing solution of theproduct in the reaction mixether was added 2.5 g. of magnesium turnings.ture, the two layers are separated and the aque- The phenylmagnesiumbromide obtained is re- Example 2 acted with 10.5 g. of cyanopyrazine.After adding ice, the complex was decomposed with ammonium chloride andthe product was extracted with ether. The ether was distilled ofi andthe benzoylpyrazine was distilled from the residue and had a boilingrange of 190-200 C./20 mm. The product was further characterized by thepreparation of the 2,4-dinitrophenylhydrazine of the benzoylpyrazine.

We claim:

1. Compounds having the general formula:

in which R is a member of the group consisting of alkyl, naphthyl andphenyl radicals which comprises reacting a member of the groupconsisting of an alkyl magnesium halide, naphthyl magnesium halide andphenyl magnesium halide with cyanopyrazine and recovering said compoundtherefrom.

6. A method of preparing a lower alkyl carbonyl pyrazine which comprisesreacting a lower alkyl magnesium bromide with cyanopyrazine andrecovering said compound therefrom.

7. A method of preparing acetylpyrazine which comprises reacting methylmagnesium bromide with cyanopyrazine and recovering said compoundtherefrom.

8. A method of preparing benzoylpyrazine which comprises reacting phenylmagnesium bromide with cyanopyrazine and recovering said compoundtherefrom.

N 0 references cited.

1. COMPOUNDS HAVING THE GENERAL FORMULA:
 5. A METHOD OF PREPARINGCOMPOUNDS HAVING THE FORMULA: